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.landbiocinc.com OncoImmnology 1635

OncoImmnology 1:9, 16351636; Dcmb 2012; 2012 Land Biocinc

AuthOrs VIew AuthOrs VIew

In recent years, a number o studies haveindicated that natural killer (NK) cells arenot merely cytotoxic lymphocytes compe-tent in containing viral and tumor spread-ing but also can be considered as crucialne-tuning eector cells during protec-tive immune responses. For instance,the exploration o the unctional linksbetween NK and dendritic cells (DCs)has shown that reciprocal activation ensuethe NK/DC interaction.1,2 Thereore, NKcells can also shape adaptive immune

responses by causing DC maturation andinfuencing the polarization o primaryT-cell responses.3 These unctions sup-port protective immune responses againstintracellular pathogens and tumors thatare most eciently promoted by Th1polarized immunity.3,4 The NK cell-mediated dierentiation and maturationo DCs primarily occurs via the release opro-infammatory cytokines by activatedNK cells, including tumor necrosis actor (TNF) and intereron (IFN).4

Conversely, once activated by DCs,

NK cells can acquire the capability o kill-ing immature myeloid DCs.1 This eectis due to the act that immature DCstypically express low levels o MHC classI molecules, which would protect themrom NK-mediated lysis. Conversely,DCs that, upon antigen uptake, undergomaturation, upregulate MHC Class I

In vivo evidence for dendritic cell lysis by NK cellsHints on improving cancer vaccines by targeting NK cell

activation

Gido Flazzo

Laboaoy o Immnology and Bioapy; Dpamn o hman Paology; univiy o Mina; Mina, Ialy

Keywords: Cancer vaccines, cytotoxic T lymphocytes, dendritic cells, natural killer cells, lymph nodes, perorin

Correspondence to: Guido Ferlazzo; Email: guido.ferlazzo@unime.it

Submitted: 07/27/12; Accepted: 07/31/12

http://dx.doi.org/10.4161/onci.21682

expression and become resistant to NKcells.1 During the process o maturation,DCs not only upregulate MHC mole-cules but also chemokine receptors, suchas CCR7, and co-stimulatory molecules.The expression o these molecules is cru-cial or the subsequent DC migration tolymph nodes as well as or the primingo T lymphocytes. Thus, it has been sug-gested that the NK-mediated killing oDCs may serve to keep in check the qual-ity and the quantity o DCs undergoing

maturation (DC editing).

5

Accordingto this model, DCs that ail to expresssucient amounts o MHC molecules,which would induce inappropriate, low-anity T-cell priming resulting either inTh2 responses or in the induction o tol-erance, would be removed by NK cells.6Indeed, in the absence o NK cells, thein vivo deault development pathway oT cells appears strongly biased towardthe acquisition o a Th2 phenotype.7

However, while in vivo evidence orDC activation by NK cells had previously

been provided,8,9

the demonstration thatautologous DC killing by NK cells is aunctionally relevant event occurring invivo has remained elusive or a long time.We addressed this issue in a recent study,showing that NK cells can ecientlyselect highly immunogenic DCs or thegeneration o optimal adaptive immune

responses in vivo.10 In an experimentalmodel o anticancer vaccination, irradi-ated tumor cells were administered aloneor together with cells devoid o MHCClass I molecules, i.e. cells capable o trig-gering NK cell activation. Adding MHC-devoid target cells in the vaccine boostedthe expansion o tumor-specic CTLs,eventually resulting in enhanced survivalo mice upon challenge with a lethal doseo tumor cells (Fig. 1). The depletion oNK cells as well as the use oPfn/ mice

(which lack the gene coding or perorin)impaired both this tumor-specic T-cellresponse and its protective role upontumor challenge.

It is noteworthy that such an enhancedantitumor immune response was stronglyassociated with a decrease in the num-ber o DCs ound in vaccine-draininglymph nodes. We indeed observed thatthe addition o MHC-devoid cells to thevaccine was consistently accompanied bya decrease o DCs in draining but not incontrolateral lymph nodes. The residual

DCs in the draining lymph node displayedhigher T-cell activating capability. Thisdecrease in the number o nodal DCs wasabrogated by depleting NK cells in mice,indicating a crucial role or NK cells inthis phenomenon. In addition, no decreaseo DCs occurred in draining lymph nodeso Pfn/ mice, strongly suggesting that

By ing an xpimnal modl o anicanc vaccinaion, av cnly ln ppo o ampion, o a

only aind by in vio daa, a naal kill cll can ain l immnognic, allgdly olognic, dndiic

cll (DC). ti in vivo lcion o immnognic DC appa o dpnd on poin and o b aociad i a mo

pociv mo-pcifc t lympocy pon.

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activated NK cells. Al logeneic tumor cellsin these cancer vaccines could be coupledwith autologous tumor cells i available.Nevertheless, since patient cancer cellsare oten not accessible, immunotherapyprotocols oreseeing the use o suitableallogeneic cells might allow to both enroll

large cohorts o cancer patients and vir-tually improve the ecacy o anticancervaccines.

References

1. Ferlazzo G, Tsang ML, Moretta L, Melioli G, SteinmanRM, Mnz C. Human dendritic cells activate restingnatural killer (NK) cells and are recognized via theNKp30 receptor by activated NK cells. J Exp Med2002; 195:343-51; PMID:11828009; http://dx.doi.org/10.1084/jem.20011149.

2. Ferlazzo G, Mnz C. Dendritic cell interactions withNK cells rom dierent tissues. J Clin Immunol2009; 29:265-73; PMID:19280325; http://dx.doi.org/10.1007/s10875-009-9283-y.

3. Martn-Fontecha A, Thomsen LL, Brett S, Gerard C,

Lipp M, Lanzavecchia A, et al. Induced recruitmento NK cells to lymph nodes provides IFN-gammaor T(H)1 priming. Nat Immunol 2004; 5:1260-5;PMID:15531883; http://dx.doi.org/10.1038/ni1138.

4. Ferlazzo G. Natural killer and dendritic cell liai-son: recent insights and open questions. ImmunolLett 2005; 101:12-7; PMID:15941591; http://dx.doi.org/10.1016/j.imlet.2005.04.015.

5. Moretta A. Natural killer cells and dendritic cells:rendezvous in abused tissues. Nat Rev Immunol2002; 2:957-64; PMID:12461568; http://dx.doi.org/10.1038/nri956.

6. Langenkamp A, Messi M, Lanzavecchia A, SallustoF. Kinetics o dendritic cell activation: impact onpriming o TH1, TH2 and nonpolarized T cells. NatImmunol 2000; 1:311-6; PMID:11017102; http://dx.doi.org/10.1038/79758.

7. Byrne P, McGuirk P, Todryk S, Mills KH. Depletiono NK cells results in disseminating lethal inection

with Bordetella pertussis associated with a reductiono antigen-speciic Th1 and enhancement o Th2,but not Tr1 cells. Eur J Immunol 2004; 34:2579-88; PMID:15307190; http://dx.doi.org/10.1002/eji.200425092.

8. Andrews DM, Scalzo AA, Yokoyama WM, Smyth MJ,Degli-Esposti MA. Functional interactions betweendendritic cells and NK cells during viral inection. NatImmunol 2003; 4:175-81; PMID:12496964; http://dx.doi.org/10.1038/ni880.

9. Mocikat R, Braumller H, Gumy A, Egeter O, ZieglerH, Reusch U, et al. Natural killer cells activated byMHC class I(low) targets prime dendritic cells toinduce protective CD8 T cell responses. Immunity2003; 19:561-9; PMID:14563320; http://dx.doi.org/10.1016/S1074-7613(03)00264-4.

10. Morandi B, Mortara L, Chiossone L, Accolla RS,Mingari MC, Moretta L, et al. Dendritic cell edit-ing by activated natural killer cells results in a moreprotective cancer-speciic immune response. PLoSOne 2012; 7:e39170; PMID:22723958; http://dx.doi.org/10.1371/journal.pone.0039170.

NK cell activation, such as the use oNK-sensitive cancer cells. In the attemptto develop novel antitumor vaccines,appropriate NK cell activation couldbe accomplished by the employment ohistotype-matched allogeneic tumor cellsexpressing MCH class I molecules thatare adequately mismatched with the NKcell inhibitory receptor repertoire o the

patient. In this scenario, allogeneic tumorcells would be recognized and killed byNK cells providing a sucient source otumor-associated antigens to be loaded onhighly immunogenic DCs, as selected by

NK cells can restrain DCs number by aperorin-dependent mechanism.

Our results indicate that, in vivo, NKcells can edit DCs or the generationo optimal adaptive immune responsesnot only by inducing DC maturationand improving DC survival, as previ-ously demonstrated,8,9 but also by kill-ing poorly immunogenic DCs.10 Cell

vaccines are under intense investigationand represent a easible and inexpensivetool or cancer immunotherapy. Ourdata suggest that cancer cell vaccinescould be improved by strategies aimed at

Figure 1. (A and B) In an xpimnal modl o anicanc vaccinaion, mic vaccinad

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